We propose a novel chemotherapeutic approach to reduce the incidence of dental caries, the most prevalent and costly oral infectious disease. Fluoride is the mainstay for the prevention of dental caries; however, as currently used, (1) fluoride offers incomplete protection against caries, and (2) does not address effectively the infectious aspect of the disease. Elevated amounts of bacterial-derived extracellular polysaccharides-EPS (Streptococcus mutans, a key contributor) and persistent low pH environment in the matrix of the biofilms are prime factors associated with the pathogenesis of dental caries and offer major targets for novel therapeutic agents. We propose a new concept of anti-caries therapy using specific combinations of cranberry flavonoids (1) to disrupt the formation of EPS and acidification of the biofilms matrix, (2) which will enhance the caries preventive effect of fluoride. Data from our USPHS/NIH supported studies have shown that aqueous extract of cranberry effectively reduced the formation of EPS and acidogenicity of S. mutans within biofilms in vitro, and the development of dental caries in vivo without displaying biocidal activity. Cranberries harbor a complex mixture of active, non-active and potentially detrimental compounds, such as organic acids. Further bioassay- guided purification studies have identified five major bioactive and structurally distinctive flavonoids in cranberries: a flavonol (quercetin-3-arabinofuranoside) and four A-type proanthocyanidins (procyanidin A2, tetramer, hexamer and nonamer). Elucidation of the particular mechanisms of action by which these compounds disrupt the ability of S. mutans to utilize sucrose to form EPS and acids is critical to further enhance their therapeutic effects; such information will guide us in selecting precisely the agents to be used in combination with fluoride for improved cariostatic activity. Thus, we propose a step-wise research plan as follows: (1) characterization of the biological actions of individual compounds and fluoride by studies on: (i) expression of S. mutans genes required for the EPS-matrix synthesis, (ii) catabolic pathway of S. mutans by specific assays on sugar uptake system and glycolytic enzymes, and (iii) retention time within biofilm; (2) identification of specific combinations of cranberry flavonoids based on their mode of action and pharmacological targets, potency and retention within biofilms; and whether the addition of fluoride can enhance the overall effects on EPS and acidogenicity, (3) testing the effects of combinations of agents on formation, biochemical, inorganic and microbial composition of multi-species biofilms on saliva-coated hydroxyapatite surface, and further selection of most effective therapies, and (4) evaluation of the effectiveness of selected combination therapies in disrupting establishment of S. mutans infection, and caries development using our rodent model. A comprehensive program ranging from basic laboratory studies to in vivo investigations in animals is offered that could result in providing new therapeutic agents working in concert with fluoride while simultaneously enhancing our understanding of the pathogenesis of dental caries.